This invention relates to therapeutic and prophylactic agents for neoplasms which comprise a fused heterocyclic compound or a pharmaceutically acceptable salt thereof as an active ingredient; to the use of such a compound in the preparation of a medicament for the treatment and prevention of neoplasms; and to a method for treatment and prevention of neoplasms which comprises administering a pharmaceutically effective amount of such a compound to a warm-blooded animal (preferably a human).
The term xe2x80x98neoplasmsxe2x80x99 in this specification includes sarcoma, various cancers, and leukemia, which include fibrosarcoma, liposarcoma, osteosarcoma, angiosarcoma, cancers of the lung, the stomach, the large intestine, the breast, the prostate gland, the kidney, the liver, the pancreas, the esophagus, the tongue, the pharynx, the bladder and ovary, brain tumors, acute leukemia, chronic leukemia, and lymphoma.
The compounds which are useful for the present invention and general methods of preparing these compounds are described in Japanese Patent Application Publication Hei 9-295970, EP 0745600 and U.S. Pat. No. 5,886,014 (all incorporated by reference). However, these descriptions about these compounds do not disclose their suppressive effects against proliferation of cancer cells. Further, these compounds have been disclosed as therapeutic or prophylactic agents for diabetes mellitus or hyperlipidemia; thus, the prior art documents differ from the present invention.
Compounds having the benzimidazole ring group are disclosed in WO 99/18081. However, the fused hetero ring has phenoxy, phenylthio, pyridyloxy or pyridylthio groups as substituents. The present invention compounds do not have such substituents.
Numerous compounds are commercially available as chemotherapeutic agents for cancer. However, it has become clear that the efficacy of currently available chemotherapeutic agents against various cancers is sometimes insufficient, i.e., in some cases cancer cells have developed natural tolerance against the therapeutic agents. Further, some therapeutic or prophylactic agents exert side effects, or make cancer cells gain tolerance during clinical use. Therefore, clinical use of chemotherapeutic agents for cancers has been complicated. Under these circumstances, novel anticancer agents have always been desired in cancer chemotherapy.
The problem to be solved by the present invention is to provide novel anticancer agents to satisfy the desire described above.
The inventors have earnestly carried out research on the synthesis of fused heterocyclic compounds, pharmaceutically acceptable salts thereof, and their pharmacological activity in order to solve this problem. The inventors have found that some fused heterocyclic compounds exhibit excellent suppressive effects against proliferation of cancer cells and that they are excellent therapeutic and prophylactic agents for cancer.
This invention comprises a therapeutic and prophylactic agent for neoplasms which comprises as active ingredient a fused heterocyclic compound of formula (I) or a pharmaceutically acceptable salt thereof: 
wherein
X is a benzimidazolyl group which is optionally substituted with 1 to 5 substituents selected from Group A;
Y is an oxygen or sulfur atom;
Z is a group selected from the following formulae: 
(hereinafter, these groups are referred to as i) 2,4-dioxothiazolidin-5-ylidenylmethyl, ii) 2,4-dioxothiazolidin-5-ylmethyl, iii) 2,4-dioxooxazolidin-5-ylmethyl, iv) 3,5-dioxooxadiazolidin-2-ylmethyl and v) N-hydroxyureidomethyl groups, respectively);
R is hydrogen, straight or branched chain C1-C6 alkyl, straight or branched chain C1-C6 alkoxy, halogen, hydroxyl, nitro, amino which is optionally substituted with one or more substituents selected from Group B and straight or branched chain C7-C11 aralkyl which is optionally substituted with one or more substituents selected from Group C;
m is an integer from 1 to 5 inclusive;
Group A comprises straight or branched chain C1-C6 alkyl, straight or branched chain C1-C6 alkoxy, straight or branched chain C7-C11 aralkyloxy, halogen, hydroxyl, straight or branched chain C1-C11 aliphatic acyloxy, straight or branched chain C1-C6 alkylthio, straight or branched chain C1-C6 halogenoalkyl, nitro, amino which is optionally substituted with one or more substituents selected from Group B, C6-C10 aryl which is optionally substituted with one or more substituents selected from Group C, and straight or branched chain C7-C11 aralkyl which is optionally substituted with one or more substituents selected from Group C;
Group B comprises straight or branched chain C1-C6 alkyl, straight or branched chain C7-C11 aralkyl, C6-C10 aryl, straight or branched chain C1-C11 aliphatic acyl, C8-C12 aromatic aliphatic acyl and C7-C11 aromatic acyl; and
Group C comprises straight or branched chain C1-C6 alkyl, straight or branched chain C1-C6 alkoxy, halogen, hydroxyl, nitro, C6-C10 aryl, straight or branched chain C1-C6 halogenoalkyl, and amino which is optionally substituted with one or more substituents selected from Group B.
Preferred compounds of formula (I) are:
(1) a fused heterocyclic compound or a pharmaceutically acceptable salt thereof wherein X is benzimidazolyl which is optionally substituted with 1 to 3 substituents selected from Group A;
(2) a fused heterocyclic compound or a pharmaceutically acceptable salt thereof wherein X is benzimidazolyl which is optionally substituted with two substituents selected from Group A;
(3) a fused heterocyclic compound or a pharmaceutically acceptable salt thereof wherein Y is an oxygen atom;
(4) a fused heterocyclic compound or a pharmaceutically acceptable salt thereof wherein Y is a sulfur atom;
(5) a fused heterocyclic compound or a pharmaceutically acceptable salt thereof wherein Z is 2,4-dioxothiazolidin-5-ylmethyl or 2,4-dioxooxazolidin-5-ylmethyl;
(6) a fused heterocyclic compound or a pharmaceutically acceptable salt thereof wherein Z is 2,4-dioxothiazolidin-5-ylmethyl;
(7) a fused heterocyclic compound or a pharmaceutically acceptable salt thereof wherein R is hydrogen, straight or branched chain C1-C4 alkyl, straight or branched chain C1C4 alkoxy, halogen, hydroxyl, nitro, amino, or straight or branched chain C7-C11 aralkyl;
(8) a fused heterocyclic compound or a pharmaceutically acceptable salt thereof wherein R is hydrogen;
(9) a fused heterocyclic compound or a pharmaceutically acceptable salt thereof wherein m is an integer from 1 to 3 inclusive;
(10) a fused heterocyclic compound or a pharmaceutically acceptable salt thereof wherein m is 1;
(11) a fused heterocyclic compound or a pharmaceutically acceptable salt thereof wherein Group A comprises straight or branched chain C1C6 alkyl, straight or branched chain C1C6 alkoxy, straight or branched chain C7-C11 aralkyloxy, halogen, hydroxyl, straight or branched chain C1-C7 aliphatic acyloxy, straight or branched chain C1C6 alkylthio and straight or branched chain C7-C11 aralkyl;
(12) a fused heterocyclic compound or a pharmaceutically acceptable salt thereof wherein Group A comprises straight or branched chain C1-C4 alkyl, straight or branched chain C1C4 alkoxy and straight or branched chain C7-C11 aralkyloxy;
(13) a fused heterocyclic compound or a pharmaceutically acceptable salt thereof wherein Group A comprises methyl, methoxy and benzyloxy;
(14) a fused heterocyclic compound or a pharmaceutically acceptable salt thereof wherein Group B comprises straight or branched chain C1C4 alkyl, straight or branched chain C7-C11 aralkyl and straight or branched chain C1-C7 aliphatic acyloxy; and
(15) a fused heterocyclic compound or a pharmaceutically acceptable salt thereof wherein Group C comprises straight or branched chain C1-C4 alkyl, straight or branched chain C1C4 alkoxy, halogen, hydroxyl, straight or branched chain C1-C4 halogenoalkyl and amino.
In addition, a preferred compound, which is included in the scope of compounds of formula (I), is a fused heterocyclic compound of formula (II) or a pharmaceutically acceptable salt thereof: 
wherein X is benzimidazolyl which is optionally substituted with 1 to 5 substituents selected from Group Axe2x80x2; and
Group Axe2x80x2 comprises straight or branched chain C1-C6 alkyl, straight or branched chain C1-C6 alkoxy, straight or branched chain C7-C11 aralkyloxy, halogen, hydroxyl, straight or branched chain C1-C7 aliphatic acyloxy, straight or branched chain C1-C6 alkylthio and straight or branched chain C7-C11 aralkyl.
In the compound of formula (II), the number of substituents selected from Group Axe2x80x2 is preferably from 1 to 3 and more preferably 2. In the compound of formula (II), the preferred Group Axe2x80x2 is a group described in (12) or (13) above which is a preferred group of the substituent Group A.
Typical compounds of this invention are listed below in JP HEI-9-295970 and in U.S. Pat. No. 5,886,014 (especially Tables in columns 24-141). However, the scope of the invention is not restricted by these compounds.
5-[4-(1-methyl-1H-benzimidazol-2-ylmethoxy)benzyl]thiazolidine-2,4-dione;
5-[4-(6-methoxy-1-methyl-1H-benzimidazol-2-ylmethoxy)benzyl]thiazolidine-2,4-dione;
5-[4-(5-methoxy-1-methyl-1H-benzimidazol-2-ylmethoxy)benzyl]thiazolidine-2,4-dione;
5-[4-(1-benzyl-1-H-benzimidazol-5-ylmethoxy) benzyl]thiazolidine-2,4-dione;
5-[4-(5-hydroxy-1,4,6,7-tetramethyl-1H-benzimidazol-2-ylmethoxy)benzyl]thiazolidine-2,4-dione;
5-[4-(5-acetoxy-1,4,6,7-tetramethyl-1H-benzimidazol-2-ylmethoxy)benzyl]thiazolidine-2,4-dione;
5-[4-(6-benzyloxy-1-methyl-1H-benzimidazol-2-ylmethoxy)benzyl]thiazolidine-2,4-dione;
5-[4-(6-chloro-1-methyl-1H-benzimidazol-2-ylmethoxy)benzyl]thiazolidine-2,4-dione;
5-[4-(6-methylthio-1-methyl-1H-benzimidazol-2-ylmethoxy)benzyl]thiazolidine-2,4-dione; and pharmaceutically acceptable salts thereof.
A salt of the compound of formula (I) can be prepared by a conventional method. Examples of the salt include hydrohalogenic acid salts such as hydrofluoride, hydrochloride, hydrobromide and hydroiodide; inorganic acid salts such as nitrate, perchlorate, sulfate and phosphate; alkanesulfonic acid salts such as methanesulfonate, trifluromethanesulfonate and ethanesulfonate; arylsulfonic acid salts such as benzenesulfonate and p-toluenesulfonate; amino acid salts such as glutamate and aspartate; and carboxylic acid salts such as acetate, fumarate, tartrate, oxalate, maleate, malate, succinate, benzoate, mandelate, ascorbate, lactate, gluconate and citrate. Preferred salts are hydrohalogenic acid salts such as hydrofluoride, hydrochloride, hydrobromide and hydroiodide and a more preferred salt is hydrochloride.
In addition, when the compound of formula (I) has a phenolic hydroxyl group, a metal salt of the compound can be prepared by a conventional method. Examples of the salt include alkali metal salts such as lithium, sodium and potassium salts; alkaline earth metal salts such as calcium, barium and magnesium salts; and inorganic salts such as an aluminum salt.
The compounds of this invention can exist in various isomeric forms. For example, certain fused heterocyclic compounds of formula (I) have asymmetric carbon(s) on the thiazolidine or oxazolidine ring and also have asymmetric carbon(s) on the substituent(s) of said compound of formula (I). Such compounds can exist as optical isomers.
Certain fused heterocyclic compounds of formula (I) can exist as stereoisomers having (R) and (S) configuration(s) on each asymmetric carbon. The present invention encompasses each pure stereoisomer and a mixture of the isomers in any ratio. A pure stereoisomer of the fused heterocyclic compound of formula (I) can be synthesized from an optically active starting material or can be obtained from a mixture of synthesized fused heterocyclic compounds of formula (I) via a conventional optical resolution technique.
When certain fused heterocyclic compounds of formula (I) are allowed to stand in the air or recrystallized, such compounds absorb or adsorb water to form a hydrate. Such hydrates are encompassed in the scope of this invention.
In addition, certain fused heterocyclic compounds of formula (I) may absorb a solvent to form a solvate. Such solvates are also encompassed in the scope of this invention.
This invention encompasses a compound (prodrug) which converts into a fused heterocyclic compound of formula (I) or a pharmaceutically acceptable salt thereof in vivo. When the fused heterocyclic compound of formula (I) has a phenolic hydroxy group, a prodrug of the compound of formula (I) is a compound wherein the hydroxyl group is protected by a protecting group that can be cleaved by a biological process such as hydrolysis in vivo.
A protecting group that can be cleaved by a biological process such as hydrolysis in vivo is a group that is capable of being cleaved by a biological process to afford a compound having a free phenolic hydroxyl group or a salt thereof. Whether a compound of formula (I) has a protecting group that can be cleaved by a biological process can easily be determined. The hydroxy-protected compound of formula (I) under investigation is intravenously administered to a test animal such as a mouse or rat and the body fluids of the test animal are thereafter studied. If the parent compound of formula (I) having a free phenolic hydroxyl group or a salt thereof is detected in the body fluids of the test animal, the hydroxy-protected compound of formula (I) under investigation is judged to be a prodrug of the compound of formula (I).
Examples of such protecting groups include 1-(lower aliphatic acyloxy) lower alkyl groups such as formyloxymethyl, acetoxymethyl, propionyloxymethyl, butyryloxymethyl, pivaloyloxymethyl, 1-formyloxyethyl, 1-acetoxyethyl, 1-propionyloxyethyl, 1-butyryloxyethyl and 1-pivaloyloxyethyl; (lower alkoxycarbonyloxy)alkyl groups such as methoxycarbonyloxymethyl, ethoxycarbonyloxymethyl, propoxycarbonyloxymethyl, isopropoxycarbonyloxymethyl, butoxycarbonyloxymethyl, isobutoxycarbonyloxymethyl, 1-(methoxycarbonyloxy)ethyl, 1-(ethoxycarbonyloxy)ethyl, 1-(propoxycarbonyloxy)ethyl, 1-(isopropoxycarbonyloxy)ethyl, 1-(butoxycarbonyloxy)ethyl, 1-(isobutoxycarbonyloxy)ethyl and 1-(t-butoxycarbonyloxy)ethyl; and phthalidyl groups such as phthalidyl, dimethylphthalidyl and dimethoxyphthalidyl.
When the group Z in the compound of formula (I) is 2,4-dioxothiazolidin-5-ylmethyl, 2,4-dioxooxazolidin-5-ylmethyl, 2,4-dioxothiazolidin-5-ylidenylmethyl or 3,5-dioxooxadiazolidin-2-ylmethyl, these groups can exist in various tautomeric forms respectively. Examples of these tautomers are shown below. 
The compounds of formula (I) include each tautomer and a mixture of tautomers. Each tautomer and a mixture of tautomers are encompassed in the scope of this invention.
Dosage forms for the compounds of formula (I) include tablets, capsules, granules, powders or syrups for oral administration; and injections, suppositories and eyedrops for parenteral administration. These dosage forms can be prepared by a method known to those skilled in the art using additives such as excipients, lubricants, binders, disintegrants, stabilizers, corrigents and diluents. Examples of excipients include organic excipients, for example, sugar derivatives such as lactose, white soft sugar, glucose, mannitol and sorbitol; starch derivatives such as corn starch, potato starch, xcex1-starch, dextrin and carboxymethylstarch; cellulose derivatives such as crystalline cellulose, low-substituted hydroxypropylcellulose, hydroxypropylmethylcellulose, carboxymethylcellulose, calcium carboxymethylcellulose, internally cross-linked sodium carboxymethylcellulose; gum arabic; dextran; pullulan; inorganic excipients, for example, silicate derivatives such as light silicic anhydride, synthetic aluminum silicate and magnesium aluminate metasilicate; phosphates such as calcium phosphate; carbonates such as calcium carbonate; and sulfates such as calcium sulfate.
Examples of lubricants include stearic acid; metal stearates such as calcium stearate and magnesium stearate; talc; colloidal silica; waxes such as beeswax and spermaceti; boric acid; adipic acid; sulfates such as sodium sulfate; glycol; fumaric acid; sodium benzoate; DL-leucine, sodium salts of fatty acids; lauryl sulfates such as sodium lauryl sulfate and magnesium lauryl sulfate; silicic acid derivatives such as silicic acid anhydride and silicic acid hydrate; and the starch derivatives described above.
Examples of binders include polyvinylpyrrolidone, macrogol (trade mark) and the excipients described above.
Examples of disintegrants include the excipients described above and chemically modified starches and celluloses such as sodium croscarmellose, sodium carboxymethylstarch; and cross-linked polyvinylpyrrolidone.
Examples of stabilizers include paraoxybenzoates such as methylparaben and propylparaben; alcohols such as chlorobutanol, benzyl alcohol and phenethyl alcohol; benzalkonium chloride; phenol derivatives such as phenol and cresol; thimerosal; dehydroacetic acid; and sorbic acid.
Examples of corrigents include sweeteners, souring agents, and flavoring agents which are usually used.
The dose of the compound of formula (I) or pharmaceutically acceptable salt thereof will vary depending on a variety of factors such as the age, symptoms of the patient and the route of administration. A suitable dosage level for oral administration is from 0.01 mg (preferably 0.1 mg) per day as a lower limit to 2000 mg (preferably 500 mg, more preferably 100 mg) per day as an upper limit for a patient (warm-blooded animal, particularly a human) and the dosage is administered either as a single unit dosage or divided into several times throughout the day depending on the symptoms of the patient. A suitable dosage level for intravenous administration is from 0.001 mg (preferably 0.01 mg) per day as a lower limit to 500 mg (preferably 50 mg) per day as an upper limit for an adult (particularly an adult human), and the dosage is administered either as a single unit dosage or divided into several times throughout the day depending on the symptoms of the patient.
The following Examples, Reference Examples, Test Examples and Formulation Examples are intended to further illustrate the present invention and are not intended to limit the scope of this invention in any manner.